Method of producing sympathomimetic activity by isopropyl-2&#39;-phenoxymethyl-2-imidazoline



United States Patent METHGD 0F PRODUCING SYh WATHGMMETHC ACTIVITY BY iSOPRt)PYL-2'-PHENOXYMETH- YL-Z-IMHDAZQLINE Don Pierre Rene Lucien Giudiceili, Fontenay-sons-Bois, seine, France, assignor to Les Laboratoires Dausse, Paris, France, a corporation of France No Drawing. Filed May 4, 1961, Ser. No. 107,640

6 Claims. (Cl. 167-65) The present invention relates to new and novel therapeutic compositions and methods of employing them adapted to exert a decongestant effect on the upper respiratory tract when administered to humans and animals, and more particularly, to such compositions containing isopropyl-2 phenoxymethyl-Z-imidazoline hydrochloride.

Imidazoline derivatives containing a phenoxy methyl group attached to the second carbon atom of the heterocycle are known. The present invention is concerned with the use of a particular member of the group, namely, isopropyl-Z'phenoxymethyl-Z-imidazoline hydrochloride, together with a pharmaceutically acceptable carrier so that it may be compounded into tablets, capsules, suppositories and liquid dose-forms.

Isopropyle2'-phenoxymethyl-2 imidazoline hydrochloride is a white solid; soluble in water and ethanol, having a melting point of 165 C. The compound has a molecular weight of 254.5 and an empirical formula of CHHHONZCI The compound is stable in both the dry form and in the final dosage form when combined with a pharmaceutically acceptable carrier.

Pharmacologically, isopropyl-Z-phenoxymethyl-2-irnidazoline hydrochloride exhibits a low order of toxicity and a high degree of therapeutic activity. Thus, the LD determined by the method of Kaerber and Behrens, in the white mouse, is 0.011 gm./kg., by the intravenous route; 0.0375 gm./kg., by the subcutaneous route and 0.0375 gm./kg. by the intraperitoneal route.

It has been found that the compound exerts a pronounced vasoconstrictive action resulting in a shrinkage in the volume of certain body organs. The order of contraction of these organs is directly related to the degree of engorgement which is in turn controlled by the volume of blood per unit area of tissue. Thus, a contraction in the volume of the dogs kidney will be observed after the intravenous injection of isopropyl-2'-phenoxyrnethyl-2- imidazoline hydrochloride which is comparable to the degree of contraction produced by anequivalent dose of epinephrine. 7

After intravenous injection of this compound in the dog, plethysmographic measurements of the paw indicates a reduction in volume of this organ. Furthermore, indirect evidence of the vasoconstrictive properties of this compoundtis obtained by the reversing of the hypotensive effects of isopgreri'itline in the dog.

It has also been found that isopropyl-2aphenoxymethyl- Z-imidazoline hydrochloride causes an anesthetic efiect when used by infiltration injection techniques, or when applied to a mucosal surface. When isopropyl 2-phenoxymethyl imidazoline hydrochloride as a solution of parts per 1000 (by Weight), is compared with an equivalent solution of cocaine hydrochloride (5 parts per 1000) for surface anesthetic activity according to the method of Reguier, a virtually identical anesthetic level was obtained. The mean result obtained by us with the said solution of isopropyl-2'-phenoxymethyl-Z-imidazoline hydrochloride and the said solution of cocaine hydrochloride, as expressed according to the rating scale of Regnier was 485 and 482 respectively. Intradermal injection of a solution of 5 parts per 1000 of procaine hydrochloride and intraderma-l injections of solutions of varying strength of isopropyl-Z'-phenoxyrnethyl-2-imidazoline hydrochloride were made in the same guinea pig. Then the duration of local anesthesia resulting from these intradermalwheals was determined. Hence the duration of local anesthesia of the respective compounds was compared by administration to the same animal. The rat ng scale of Moukhtar was utilized to evaluate the level of anesthesia produced by the respective test compounds. The 5: 1000 solution of procaine hydrochloride had a rating of 37, While the 5:1000 solution in isopropyl-2'-phenoxymethyl-Z-imidazoline hydrochloride had a rating of 75 thereby establishing that the product of the present invention is approximately five times more active as a local infiltrating anesthetic than is procaine.

When the present compound is tested for its conduction anesthetic properties according to the method Quevauvil ler, its activity as a conduction anesthetic is less than that of procaine in equivalent concentrations.

lsopropyl-2'-phenoxymethyl-Z imidazoline hydrochloride is not irritating to tissues when injected in concentrae tions of 0.1 percent, or less, as evidenced by intradermal injection into the rabbits ear. The absence of local tissue irritation after intradermal injection into the rabbit car, was. confirmed by the absence of a blue-spot at themjection site when trypan blue is injected intravenously.

' Similarly, daily instillation into a rabbits eye (utilizing the other eye as a control), of a 0.5 percent solution of the compound caused no local irritation.

The compound also exerts a mild sedative, central nervous system action and also produces a mydriasis, both on local contact with the cornea as well as after intravenous injection.

Clinical congestion of the upper respiratory tract may occur as a result of a local tissue inflammatory response ova hypersecretory activity or a local irritant action. The underlying etiology may be acute or chronic infection or an imbalance of the nervous system. Whatever the cause, it has been found that the compositions of the present invention exert a desirable and beneficial decongestant eifect without causing unwanted sidereactions. Thus, the use of these products has resulted in relief of the congestion to the upper respiratory tract with a consequent reduction in the morbidity of patients suffering from acute rhinitis, rhinopharyngitis, chronic hypertropic rhinitis, purulent sinusitis and asthmatic rhinitis. The latent period before the therapeutic effect was noted was from five to ten minutes and the duration of action of a single dose was from four to six hours. The use of this medication has a rather good patient acceptability.

When it is desired to use isopropyl-Z'-phenoxymethyl-2- imidazoline hydrochloride to combat the symptoms of congestion of the upper respiratory tract, it is administered in the form of a tablet, capsule, suppository, or a solution, by either the parenteral, or topical routes. When the solid oral dose forms are desired, the active ingredient must be mixed with a compatible, pharmaceutically acceptable carrier, as, for example, powdered starch, powdered lactose or powdered sucrose, and to this is added a granulating agent, such as gum arabic or gum tragacanth, and a lubricating agent, such as magnesium stearate. After proper granulation, the mixture is compressed into tablets of the desired size and shape, or filled into capsules. The range of dosage to be employed for efiective therapy is from 0.1 mg. to 5 mg. per unit dose, and this is administered several times daiiy, depending upon the individual patients needs.

Suppositories are prepared by mixing the active ingredient with a suitable suppository base, as for example, the polyoxyethylene glycols (which are known to commerce as Carbowax), or cocoa butter, or glycerine-gelatine. mixtures. Whatever the base selected, the manufacturing steps remain the same and these comprise the mixture of the active ingredient with a suitable quantity of the base which is then molded into the proper shape and size so that each unit dose contains from 0.1 mg. to mg. of active compound.

Solutions intended for oral administration are made by dissolving the active compound in a suitable vehicle such as syrup, sherry Wine, mixtures of ethanol and Water, so that a concentration of ethanol is from five to twenty percent (by weight) glycerine, propylene glycol or mixtures of these. To the solution may be added suitable coloring and flavoring, as desired. The solutions are stable and readily acceptable to the patient. The concentration of active'ingredient in these solutions should be such that the range is from 0.1 mg. to 5 mg. per unit dose.

Parenteral solutions, as well as solutions for topical installation are prepared by dissolving the active ingredient in physiologic saline solution or Ringers solution. The concentration of active ingredients in such solutions is from one to five parts per thousand (by weight). These solutions may be sterilized by autoclaving or by any other acceptable technique. The solutions intended for parenteral use are packaged into 1 cc. and 2 cc. glass ampules, while the solution intended to be used as a topical instillation may be administered as a drop or a nebulized spray.

The clinical use of isopropyl-2-phenoxymethyl-2-irnidazoline hydrochloride, administered as a nasal-drop or a nebulized spray, in order to treat the. symptomatology arising from congestion of the upper respiratory tract in patients with acute rhinitis, rhinopharyngitis, chronic hypertrophic rhinitis, purulent sinusitis, asthmatic rhinitis, coryza and chronic vasomotor rhinitis, revealed a high degree of clinical efiicacy. The drug was found to be an effective, fast-acting and well tolerated decongestant with a highly desirable prolonged duration of action and excellent patient acceptance. These results were confirmed by comparative clinical study, utilizing a double-blind experimental technique.

Thus, through the utilization of the compositions of the present invention is clinical practice, a new means of obtaining a highly desirable and effective decongestant action in combating the symptomatology arising from congestion of the upper respiratory tract results. The high incidence of this symptomatology and the crippling effects of the morbidity arising from this pathologic state are well known and require no emphasis. The products of the present invention provide a convenient and effective answer to the long existing clinical problem of reliably correcting this state, without superimposing noxious and undesirable side reactions.

The following examples are given for the purpose of illustrating the invention:

Example 1 To prepare tablets of isopropyl-2-phenoxymethy1-21 imidazoline hydrochloride gms. of the compound are mixed with 200 gms. of powdered corn starch and to this is added gms. of powdered lactose and 0.5 gm. of gum tragacanth. The mixture is uniformly Wetted with a solution of twenty parts of ethanol and 80 parts of water. The uniformly moistened mass is then passed through a No. 16 mesh sieve and the resulting granules dried at temperatures not exceeding C. To the dry granular material is then added 0.35 gm. of magnesium stearate and the resulting mixture mechanically compressed into appropriately shaped tablets each containing 1 mg. of isopropyl-2'-phenoxymethyl-Z-imidazoline hydrochloride. Tablets may be prepared containing both a larger and lesser quantity of active ingredient, with a range per unit dose from 0.1 mg. to 5 mg.

Other pharmaceutically accepted salts of the base may be employed instead of the hydrochloride.

4 Example 2 Capsules may be prepared, so that each unit dose contains not less than 0.1 mg. and not more than 5 mg. with a preferred concentration of 1 mg. of isopropyl-2-phenoxymethyl-Z-imidazoline hydrochloride. The appropriate quantity of active ingredient, as for example, 10 grams, is mixed with gms. of powdered lactose and the mixture filled into capsules of the appropriate size and shape, which are administered several times daily.

Example 3 Solutions of oral administration may be prepared by dissolving isopropyl-2'-phenoxymethyl-2imidazoline hydrochloride in a non-toxic vehicle'or carrier as for example, Water, ethanol, glycerine, propylene glycol, polyoxyethylene glycol, or mixtures of these, to which is added suitable flavoring and coloring agents. The concentration of active ingredients should be adjusted so that each unit dose consists of 5 cc. (1 teaspoonful) and contains from 0.1 mg. to 5 mg. of the active ingredient with a preferred concentration of 1 mg. per unit dose.

Example 4 A solution to be used for instillation into the nasal fossae as a drop or nebulized or aerosolized spray is prepared by dissolving one gram of isopropyl-2'-phenoxymethyl-2imidazoline hydrochloride and 8 gms. of sodium chloride in one liter of distilled water. The range in concentration of active ingredient of a solution intended for these purposes may be from 0.1 mg. to 5 mg. per cc. of

solution with a preferred concentration of 1 mg. per cc. of

solution.

An alternate vehicle may be Ringers Solution and when this is used, .the active ingredient is dissolved directly therein. The same range in concentration and dosage as described above is utilized.

The solution intended for local instillation into the nasal fossae or to be used as a spray may be packed in one or two ounce glass bottles.

Example 5 When it is desired to achieve a local decongestant efiect on the upper respiratory system, a solution of isopropyl 2' phenoxymethyl Z-imidazoline hydrochloride prepared as described in Example 4 above, is instilled into the nasal fossae in the form of a drop or as a nebulized spray. If the active ingredient is to be. used in the form of a nose drop, then one to five drops are instilled into each nostril one to six times daily. A prompt decongestant effect will be observed with a diminution of excessive secretions, thereby facilitating physiologic respiration. Absorption of the drug from the respiratory track will not result in any cardio-toxic side reactions nor any interference with the central nervous system. A mild anesthetic effect will be present, thereby reducing the local irritant sensations arising from the particular pathology present, which facilitates the normalizing process. Toleranceto the drug does not develop and it may be used for continued periods of time without modification of the origi nal dosage.

An alternate and equally eifective method of administration of the drug is the use of a nebulized or aerosolized spray. This method of drug administration has certain preferential advantages since the droplets are dispersed and finely divided so that they penetrate through the narrowed nasal tissue channels. Furthermore, the ordinary inspiration will carry the fine-droplets of medication to the deeper recesses of the upper respiratory tract thereby causing the active ingredient to exert its local decongestant efiect over a Wider area. When nebulization is desired, the solution of the drug as prepared according to Example 4 above, is transferred to a conventional nebulizing apparatus and the flow of droplets directed either toward the hack of the throat or into each nostril. The frequency of instillation will depend upon the patients own needs but that the vast majority of patients will receive elfective and continuing relief utilizing this means of administration one to six times daily.

Example 7 The tablets, capsules, suppositories, liquid oral-dosage forms, and the parenteral solution, prepared as described in Examples 1, 2, 3, 4, and above, may be used to effect a decongestant action either alone or in combination with one another. A prompt and sustained decongestant eifect is observed after the administration of these oral dose forms without aiiecting the cardiovascular or central nervous systems. Thus, the medication may be administered to patients receiving other cardiovascular medicinals Without specific interrerence with the desired therapeutic effect, although the necessary precautions which are observed on the part of good clinical practice in the treatment of the patient with cardiac disease must be followed. When the drug is used orally or by injection, the frequency of administration is from one to six times daily, dependent on the patients needs.

It is not desired to be limited except as set forth in the following claims, the above description being by way of illustration of the invention.

What is claimed is:

1.. A method of producing peripheral sympathomimetic activity in a patient which comprises administering to said patient a pharmeceutical composition containing a therapeutically effective amount of a compound selected from the group consisting of isopr0py1-2'-phenoxymethyl-2- irnidazoline and its pharmeceutically acceptable salts.

2. A method of producing peripheral sympathomimetic activity in a patient which comprises administering to said patient a pharmeceutical composition containing a therapeutically effective amount of isopropyl-2-phenoxymethyl-Z-imidazoline hydrochloride.

3. A method of producing peripheral sympathomimetic activity in a patient which comprises administering to said patient a pharmaceutical composition in the form of a decongestant comprising a pharmaceutical carrier and from 0.1 to 5 mg. per unit dosage. form of a compound selected from the group consisting of isopropyl-Z'-phenoxymethyl- Z-irnidazoiine and its pharmaceutically acceptable salts.

A method of producing peripheral sympathomimetic activity in a patient which comprises administering to said patient a pharmaceutical composition in the form of a decongestant comprising in unit dosage form a pharmaceutical carrier and from 0.1 to 5 mg. of isopropyl-2- phenoxymethyl-Z-imidazoline hydrochloride.

5. A method of producing peripheral sympathomimetic activity in a patient which comprises administering to said patient a pharmaceutical decongestant tablet comprising a solid pharmaceutical carrier and from 0.1 to 5 mg. of isoropyl2'-phenoxymethyl-2-imidazoline hydrochloride.

6. A method of producing peripheral sympathomimetic activity in a patient which comprises administering to said patient a liquid pharmaceutical decongestant containing a liquid pharmaceutical carrier and from 0.1 to 5 mg. per 5 cc. of isopropyl-Z'-phenoxymethyl-2-imidazoline hydrochloride.

References Cited by the Examiner Djerassi, Chem. Abs, vol. 41, 1947, page 6241(c), citing J.A.C.S. 69, 1688-92, 1947.

Goodman and Gilman, The Pharmacological Basis of Therapeutics, 1955, pages 663-664.

Krantz and Carr, Pharmacologic Principles of Medical Practice, 1954, page 622.

Scholz, Ind. and Eng. Chem., vol. 37, No. 2, 1945, page 122.

Sonn, Chem. Abst., vol. 33, p. 4380.

JULIAN S. LEVITT, Primary Examiner.

M. O. WOLK, IRVING MARCUS, LEWIS GOTTS,

Examiners. 

1. A METHOD OF PRODUCING PERIPHERAL SYMPATHOMIMETIC ACTIVITY IN A PATIENT WHICH COMPRISES ADMINISTERING TO SAID PATIENT A PHARMECEUTICAL COMPOSITION CONTAINING A THERAPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF ISOPROPYL-2''-PHENOXYM,ETHYL-2IMIDAZOLINE AND ITS PHARMECEUTICALLY ACCEPTABLE SALTS. 